The objective of this research program is to investigate the use of negative pi-meson (pion) beams for the radiotherapy of human malignant neoplasms, utilizing the Stanford Medical Pion Generator (SMPG), a unique cylindrical geometry superconducting pion channel which was designed and constructed at Stanford under NSF Grant GI-35007 and has been successfully tested under NCI Grant CA-13083. The 60 individual pion beams of the SMPG will provide great flexibility in treating precisely defined tumor volumes. We propose to carry out this investigation by (1) developing a pion therapy facility at the Stanford Medical Center using the electron linear accelerator and the four SMPG's of improved design requested in this application. While the design, fabrication, installation and testing of this equipment is in progress, we propose (2) to conduct a research program at the Stanford High Energy Physics Laboratory using the prototype SMPG to study the radiobiologic characteristics of multiport irradiation with the SMPG, (3) to develop and test instrumentation for pion dosimetry, (4) to computerize the control of relevant treatment parameters, (5) to develop an integrated treatment planning and patient treatment system. When the facility is operational, clinical studies will be initiated with Phase I feasibility studies (6) on selected patients with far-advanced malignant neoplasms. Phase II non-randomized clinical studies (7) will investigate the curative potential of pion beam radiotherapy for tumors not now amenable to surgical extirpation or to curative megavoltage irradiation. Phase III randomized clinical trials (8) will compare the efficacy of multiport pion beam irradiation with that of megavoltage x-ray irradiation in a spectrum of malignant neoplasms currently suboptimally managed by conventional radiotherapy. During all three phases of clinical studies, ongoing dosimetry, radiobiology and treatment planning programs will develop basic information for pion therapy as well as providing support for the clinical studies.